The current dramatic increase in congenital syphilis (CS) is a reminder of the existing ignorance about this form of syphilis. The lack of an adequate animal model has so far prevented the delineation of factors contributing to the pathogenesis and immunology of the disease. In previous studies in guinea pigs we have reproducibly obtained transplacental infection with T. pallidum. This was confirmed by serology, infectivity test in rabbits, and polymerase chain reaction. In utero-infected guinea pig neonates responded immunologically in an identical manner to congenitally infected human infants, with early production of specific IgM antitreponemal antibodies, circulating immune complexes and rheumatoid factor. We, and others, have also shown that congenital syphilis is associated with T cell activation and an increased level of CD4+ TH lymphocytes. Here we propose to study in the experimental model previously unexplored immunopathological aspects of the disease. How it is modulated by the timing of maternal infection during gestation. How it affects the immunocompetence of the infected host during development. Inasmuch as the experimental model shows several morphological, physiological and immunological features similar to humans, it is anticipated that the results of these studies will be relevant to natural CS.